Thyroid-Specific Enhancer-Binding Protein/NKX2.1 Is Required for the Maintenance of Ordered Architecture and Function of the Differentiated Thyroid

Kusakabe, Takashi; Kawaguchi, Akio; Hoshi, Nobuo; Kawaguchi, Rumi; Hoshi, Seiji; Kimura, Shioko

doi:10.1210/me.2005-0327

Cited by 100 publications

(102 citation statements)

References 37 publications

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“…In the only other paper describing thyroid histology in a patient with an NKX2-1 mutation, no abnormalities were found [Maquet et al, 2009]. In contrast, the histological alterations found in our patient were very similar to those described in adult mice of the thyroid follicular cell-specific conditional KO mouse line Nkx2-1(fl/fl);TPO-Cre [Kusakabe et al, 2006], which suggested that NKX2-1 was required to maintain the normal architecture and function of the differentiated thyroid gland. Our results support a role for NKX2-1 in normal thyroid follicle structure in humans.…”

Section: Discussionsupporting

confidence: 78%

NKX2-1mutations leading to surfactant protein promoter dysregulation cause interstitial lung disease in “Brain-Lung-Thyroid Syndrome”

et al. 2010

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NKX2-1 (NK2 homeobox 1) is a critical regulator of transcription for the surfactant protein (SP)-B and -C genes (SFTPB and SFTPC, respectively). We identified and functionally characterized two new de novo NKX2-1 mutations c.493C>T (p.R165W) and c.786_787del2 (p.L263fs) in infants with closely similar severe interstitial lung disease (ILD), hypotonia, and congenital hypothyroidism. Functional analyses using A549 and HeLa cells revealed that NKX2-1-p.L263fs induced neither SFTPB nor SFTPC promoter activation and had a dominant negative effect on wild-type (WT) NKX2-1. In contrast, NKX2-1-p.R165W activated SFTPC, to a significantly greater extent than did WT NKX2-1, while SFTPB activation was only significantly reduced in HeLa cells. In accordance with our in vitro data, we found decreased amounts of SP-B and SP-C by western blot in bronchoalveolar lavage fluid (patient with p.L263fs) and features of altered surfactant protein metabolism on lung histology (patient with NKX2-1-p.R165W). In conclusion, ILD in patients with NKX2-1 mutations was associated with altered surfactant protein metabolism, and both gain and loss of function of the mutated NKX2-1 genes on surfactant protein promoters were associated with ILD in "Brain-Lung-Thyroid syndrome".

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Section: Discussionsupporting

confidence: 78%

NKX2-1mutations leading to surfactant protein promoter dysregulation cause interstitial lung disease in “Brain-Lung-Thyroid Syndrome”

et al. 2010

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“…It is possible that impaired development of telencephalic vasculature in the Sey Dey mice is a result of impaired VEGF signaling. The role of Nkx2.1 and Pax6 in angiogenesis is not restricted to the CNS but seems more generalized and affects the lung, eye and cardiopulmonary system [39][40][41] .…”

Section: Compartmental Influences On Telencephalic Angiogenesismentioning

confidence: 99%

Compartment-specific transcription factors orchestrate angiogenesis gradients in the embryonic brain

et al. 2008

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Prevailing notions of cerebral vascularization imply that blood vessels sprout passively into the brain parenchyma from pial vascular plexuses to meet metabolic needs of growing neuronal populations. Endothelial cells, building blocks of blood vessels, are thought to be homogeneous in the brain with respect to their origins, gene expression patterns and developmental mechanisms. These current notions that cerebral angiogenesis is regulated by local environmental signals contrast with current models of cell-autonomous regulation of neuronal development. Here we demonstrate that telencephalic angiogenesis in mice progresses in an orderly, ventral-to-dorsal gradient regulated by compartment-specific homeobox transcription factors. Our data offer new perspectives on intrinsic regulation of angiogenesis in the embryonic telencephalon, call for a revision of the current models of telencephalic angiogenesis and support novel roles for endothelial cells in brain development.Brain development is supported by concomitant development of brain vasculature. However, blood vessels or endothelial cells are generally considered to lack molecular diversity in the embryonic or mature CNS 1,2 . Currently, it is believed that once the perineural plexuses on the pial surface (pial vessels) surrounding the neural tube are produced, cerebral vasculature develops further by passive vessel sprouting into the brain parenchyma in response to increased tissue mass and oxygen demand 1,2 . Although classical studies identified a ventral to dorsal temporal developmental angiogenesis gradient in the telencephalon 3 , the sequence of angiogenesis was considered to merely shadow neurogenesis and neuronal maturation. Similarly, although shared mechanisms regulating vascular and neuronal development have been recognized 4 , the canonical principles of neuronal development are not seen as applicable to CNS angiogenesis.

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“…Because the Synapsin I promoter becomes active only in terminally differentiated neurons (Hoesche et al, 1993), Cre-mediated recombination deletes the Ttf1 gene only from postmitotic neurons. Mice carrying floxed Ttf1 alleles, produced by one of our laboratories, were described recently (Kusakabe et al, 2006). Crossing these two mutant lines generated hemizygote SynCre mice (SynCreϩ/Ϫ) carrying one floxed allele (Ttf1 flox/ϩ).…”

Section: Animalsmentioning

confidence: 99%

“…The primers used to detect the WT and floxed alleles (sense 5Neo2, 5Ј-TGCCGTGTAAACACGAGGAC-3Ј; and antisense 3Neo2, 5Ј-GACTCTCAAGCAAGTCCATCC-3Ј) were those described recently (Kusakabe et al, 2006). The PCR conditions used consisted of an initial activation step of 5 min at 95°C and 36 cycles as follows: 30 s of denaturing at 94°C, 30 s of annealing at 60°C, a 1 min extension at 72°C, and a final extension of 10 min at 72°C.…”

Section: Genotypingmentioning

confidence: 99%

Deletion of theTtf1Gene in Differentiated Neurons Disrupts Female Reproduction without Impairing Basal Ganglia Function

Mastronardi¹,

Smiley²,

Raber³

et al. 2006

J. Neurosci.

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Thyroid transcription factor 1 (TTF1) [also known as Nkx2.1 (related to the NK-2 class of homeobox genes) and T/ebp (thyroid-specific enhancer-binding protein)], a homeodomain gene required for basal forebrain morphogenesis, remains expressed in the hypothalamus after birth, suggesting a role in neuroendocrine function. Here, we show an involvement of TTF1 in the control of mammalian puberty and adult reproductive function. Gene expression profiling of the nonhuman primate hypothalamus revealed that TTF1 expression increases at puberty. Mice in which the Ttf1 gene was ablated from differentiated neurons grew normally and had normal basal ganglia/hypothalamic morphology but exhibited delayed puberty, reduced reproductive capacity, and a short reproductive span. These defects were associated with reduced hypothalamic expression of genes required for sexual development and deregulation of a gene involved in restraining puberty. No extrapyramidal impairments associated with basal ganglia dysfunction were apparent. Thus, although TTF1 appears to fulfill only a morphogenic function in the ventral telencephalon, once this function is satisfied in the hypothalamus, TTF1 remains active as part of the transcriptional machinery controlling female sexual development.

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Thyroid-Specific Enhancer-Binding Protein/NKX2.1 Is Required for the Maintenance of Ordered Architecture and Function of the Differentiated Thyroid

Cited by 100 publications

References 37 publications

NKX2-1mutations leading to surfactant protein promoter dysregulation cause interstitial lung disease in “Brain-Lung-Thyroid Syndrome”

NKX2-1mutations leading to surfactant protein promoter dysregulation cause interstitial lung disease in “Brain-Lung-Thyroid Syndrome”

Compartment-specific transcription factors orchestrate angiogenesis gradients in the embryonic brain

Deletion of theTtf1Gene in Differentiated Neurons Disrupts Female Reproduction without Impairing Basal Ganglia Function

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